Methods of treating nausea utilizing semi-solid delivery vehicle compositions comprising granisetron

ABSTRACT

A semi-solid delivery vehicle contains a polyorthoester and an excipient, and a semi-solid pharmaceutical composition contains an active agent and the delivery vehicle. The pharmaceutical composition may be a topical, syringable, or injectable formulation; and is suitable for local delivery of the active agent. Methods of treatment are also disclosed.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.16/751,066, filed Jan. 23, 2020, which is a continuation of U.S.application Ser. No. 16/433,996, filed Jun. 6, 2019, which is acontinuation of U.S. application Ser. No. 15/897,093, filed Feb. 14,2018, now U.S. Pat. No. 10,357,570, issued Jul. 23, 2019, which is acontinuation of U.S. application Ser. No. 15/269,856, filed Sep. 19,2016, now U.S. Pat. No. 9,913,910, issued Mar. 13, 2018, which is acontinuation of U.S. application Ser. No. 14/253,615, filed Apr. 15,2014, now abandoned, which is a continuation of U.S. application Ser.No. 13/552,083, filed Jul. 18, 2012, now U.S. Pat. No. 8,715,710, issuedMay 6, 2014, which is a continuation of U.S. application Ser. No.12/564,881, filed Sep. 22, 2009, now U.S. Pat. No. 8,252,304, issuedAug. 28, 2012, which is a continuation of U.S. application Ser. No.10/953,841, filed Sep. 28, 2004, now abandoned, all of which are herebyincorporated by reference in their entireties.

BACKGROUND OF THE INVENTION Field of the Invention

This invention relates to semi-solid delivery vehicles comprising apolyorthoester and an excipient, and to controlled releasepharmaceutical compositions comprising the delivery vehicle and anactive agent. The pharmaceutical compositions may be in the form of atopical, syringable, or injectable formulation for local controlleddelivery of the active agent.

Description of the Prior Art

A large class of active agents such as antibiotics, antiseptics,corticosteroids, anti-neoplastics, and local anesthetics may beadministered to the skin or mucous membrane by topical application, orby injection. The active agent may act locally or systemically. Topicaldelivery may be accomplished through the use of compositions such asointments, creams, emulsions, solutions, suspensions and the like.Injections for delivery of the active agents include solutions,suspensions and emulsions. All of these preparations have beenextensively used for delivery of active agents for years. However, thesepreparations suffer the disadvantage that they are short-acting andtherefore they often have to be administered several times in a day tomaintain a therapeutically effective dose level in the blood stream atthe sites where the activity/treatment is required.

In recent years, a great deal of progress has been made to developdosage forms which, after their administration, provide a long-termtherapeutic response. These products may be achieved bymicroencapsulation, such as liposomes, microcapsules, microspheres,microparticles and the like. For this type of dosage forms, the activeagents are typically entrapped or encapsulated in microcapsules,liposomes or microparticles which are then introduced into the body viainjection or in the form of an implant. The release rate of the activeagent from this type of dosage forms is controlled which eliminates theneed for frequent dosing. However their manufacture is cumbersome whichoften results in high costs. In addition, they, in many cases, have lowreproducibility and consequently lack of reliability in their releasepatterns. Furthermore, if an organic solvent is used in themanufacturing process, there could be organic solvent residues in thecompositions which may be highly toxic. The use of an organic solvent isalso undesirable for environmental and fire hazard reasons.

Interest in synthetic biodegradable polymers for the delivery oftherapeutic agents began in the early 1970's with the work of Yolles etal., Polymer News, 1, 9-15 (1970) using poly(lactic acid). Since thattime, numerous other polymers have been prepared and investigated asbioerodible matrices for the controlled release of active agents. U.S.Pat. Nos. 4,079,038, 4,093,709, 4,131,648, 4,138,344, 4,180,646,4,304,767, 4,946,931, and 5,968,543 disclose various types ofbiodegradable or bioerodible polymers which may be used for controlleddelivery of active agents. Many of these polymers may appear in the formof a semi-solid. However the semi-solid polymer materials are often toosticky. As a result, the active agents frequently cannot be easily andreliably released from the semi-solid polymer materials.

SUMMARY OF THE INVENTION

A first objective of the present invention is to provide a semi-soliddelivery vehicle which comprises a polyorthoester and an excipient. Theexcipient is readily miscible with the polyorthoester and the resultingsemi-solid delivery vehicle has a smooth and flowable texture. Thepolyorthoesters suitable for the invention are represented by formula Iand formula II below.

Another objective of the present invention is to provide a controlledrelease semisolid pharmaceutical composition for local controlleddelivery of an active agent. The composition comprises an active agentand the semi-solid delivery vehicle.

A further objective of the present invention is to provide a semi-solidsyringable or injectable composition for the controlled delivery oflocally acting active agents, in particular local anesthetics.

The polyorthoester can be homogeneously mixed with the excipient at roomtemperature without the use of a solvent. In another variation of theprocess, the polyorthoester can be homogeneously mixed with theexcipient at between about 5 and 200° C., more preferably between about20 and 150° C., and most preferably between about 25 and 100° C. In onevariation, the polyorthoester can be at one temperature, for example atabout 70° C., and the excipient can be at a different temperature, forexample at about 120° C., and the two components are mixed to attain afinal temperature that is above room temperature. The desiredtemperatures for each of the two components will be based on the type ofthe polyorthoester and the excipient selected. The resulting semi-soliddelivery vehicle and controlled-release pharmaceutical compositions havea useful texture and viscosity, and the release rate of the active agentfrom the compositions can also be conveniently and reliably adjusted toaccommodate the desired therapeutic effect.

Thus, in a first aspect, this invention provides a semi-solid deliveryvehicle, comprising:

(a) a polyorthoester of formula I or formula II:

where:R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c areindependently integers of 1 to 5;R* is a C₁₋₄ alkyl;n is an integer of at least 5; andA is R¹, R², R³, or R⁴, where

R¹ is:

where:p is an integer of 1 to 20;R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:s is an integer of 0 to 30;t is an integer of 2 to 200; andR⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:x is an integer of 0 to 30;y is an integer of 2 to 200;R⁸ is hydrogen or C₁₋₄ alkyl;R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and R⁴ is a diol containing at least onefunctional group independently selected from amide, imide, urea, andurethane groups;in which at least 0.01 mol percent of the A units are of the formula R¹,and

(b) a pharmaceutically acceptable, polyorthoester-compatible liquidexcipient selected from polyethylene glycol ether derivatives having amolecular weight between 200 and 4000, polyethylene glycol copolymershaving a molecular weight between 400 and 4000, mono-, di-, ortri-glycerides of a C₂₋₁₉ aliphatic carboxylic acid or a mixture of suchacids, alkoxylated tetrahydrofurfuryl alcohols and their C₁₋₄ alkylethers and C₂₋₁₉ aliphatic carboxylic acid esters, and biocompatibleoils.

In a second aspect, this invention provides a controlled releasesemi-solid pharmaceutical composition comprising:

(a) an active agent; and

(b) as a delivery vehicle, the semi-solid delivery vehicle describedabove.

In a third aspect, this invention provides a method of treating adisease state treatable by controlled release local administration of anactive agent, in particular treating pain by administration of a localanesthetic, comprising locally administering a therapeutically effectiveamount of the active agent in the form of the pharmaceutical compositiondescribed above.

In a fourth aspect, this invention provides a method of treating adisease state treatable by controlled release local administration of anactive agent, in particular treating or preventing of nausea and/oremesis by administration of a antiemetic agent, comprising locallyadministering a therapeutically effective amount of the active agent inthe form of the pharmaceutical composition described above.

DETAILED DESCRIPTION OF THE INVENTION Definitions

Unless defined otherwise in this specification, all technical andscientific terms are used herein according to their conventionaldefinitions as they are commonly used and understood by those ofordinary skill in the art of synthetic chemistry, pharmacology andcosmetology.

“Active agent” includes any compound or mixture of compounds whichproduces a beneficial or useful result. Active agents aredistinguishable from such components as vehicles, carriers, diluents,lubricants, binders and other formulating aids, and encapsulating orotherwise protective components. Examples of active agents and theirpharmaceutically acceptable salts, are pharmaceutical, agricultural orcosmetic agents. Suitable pharmaceutical agents include locally orsystemically acting pharmaceutically active agents which may beadministered to a subject by topical or intralesional application(including, for example, applying to abraded skin, lacerations, puncturewounds, etc., as well as into surgical incisions) or by injection, suchas subcutaneous, intradermal, intramuscular, intraocular, orintra-articular injection. Examples of these agents include, but notlimited to, anti-infectives (including antibiotics, antivirals,fungicides, scabicides or pediculicides), antiseptics (e.g.,benzalkonium chloride, benzethonium chloride, chlorhexidine gluconate,mafenide acetate, methylbenzethonium chloride, nitrofurazone,nitromersol and the like), steroids (e.g., estrogens, progestins,androgens, adrenocorticoids, and the like), therapeutic polypeptides(e.g. insulin, erythropoietin, morphogenic proteins such as bonemorphogenic protein, and the like), analgesics and anti-inflammatoryagents (e.g., aspirin, ibuprofen, naproxen, ketorolac, COX-1 inhibitors,COX-2 inhibitors, and the like), cancer chemotherapeutic agents (e.g.,mechlorethamine, cyclophosphamide, fluorouracil, thioguanine,carmustine, lomustine, melphalan, chlorambucil, streptozocin,methotrexate, vincristine, bleomycin, vinblastine, vindesine,dactinomycin, daunorubicin, doxorubicin, tamoxifen, and the like),narcotics (e.g., morphine, meperidine, codeine, and the like), localanesthetics (e.g., the amide- or anilide-type local anesthetics such asbupivacaine, dibucaine, mepivacaine, procaine, lidocaine, tetracaine,and the like), antiemetic agents such as ondansetron, granisetron,tropisetron, metoclopramide, domperidone, scopolamine, and the like,antiangiogenic agents (e.g., combrestatin, contortrostatin, anti-VEGF,and the like), polysaccharides, vaccines, antigens, DNA and otherpolynucleotides, antisense oligonucleotides, and the like. The presentinvention may also be applied to other locally acting active agents,such as astringents, antiperspirants, irritants, rubefacients,vesicants, sclerosing agents, caustics, escharotics, keratolytic agents,sunscreens and a variety of dermatologies including hypopigmenting andantipruritic agents. The term “active agents” further includes biocidessuch as fungicides, pesticides, and herbicides, plant growth promotersor inhibitors, preservatives, disinfectants, air purifiers andnutrients. Pro-drugs of the active agents are included within the scopeof the present invention.

“Alkyl” denotes a linear saturated hydrocarbyl having from one to thenumber of carbon atoms designated, or a branched or cyclic saturatedhydrocarbyl having from three to the number of carbon atoms designated(e.g., C₁₋₄ alkyl). Examples of alkyl include methyl, ethyl, n-propyl,isopropyl, cyclopropyl, n-butyl, t-butyl, cyclopropylmethyl, and thelike.

“Alkylene” denotes a straight or branched chain divalent, trivalent ortetravalent alkylene radical having from one to the number of carbonatoms designated, or a branched or cyclic saturated cycloalkylenylhaving from three to the number of carbon atoms designated (e.g., c₁₋₄alkylenyl, or c₃₋₇ cycloalkylenyl), and include, for example1,2-ethylene, 1,3-propylene, 1,2-propylene, 1,4-butylene, 1,5-pentylene,1,6-hexylene, 1,2,5-hexylene, 1,3,6-hexylene, 1, 7-heptylene, and thelike.

“Bioerodible” and “bioerodibility” refer to the degradation, disassemblyor digestion of the polyorthoester by action of a biologicalenvironment, including the action of living organisms and most notablyat physiological pH and temperature. A principal mechanism forbioerosion of the polyorthoesters of the present invention is hydrolysisof linkages between and within the units of the polyorthoester.

“Comprising” is an inclusive term interpreted to mean containing,embracing, covering or including the elements listed following the term,but not excluding other unrecited elements.

“Controlled release”, “sustained release”, and similar terms are used todenote a mode of active agent delivery that occurs when the active agentis released from the delivery vehicle at an ascertainable andcontrollable rate over a period of time, rather than dispersedimmediately upon application or injection. Controlled or sustainedrelease may extend for hours, days or months, and may vary as a functionof numerous factors. For the pharmaceutical composition of the presentinvention, the rate of release will depend on the type of the excipientselected and the concentration of the excipient in the composition.Another determinant of the rate of release is the rate of hydrolysis ofthe linkages between and within the units of the polyorthoester. Therate of hydrolysis in turn may be controlled by the composition of thepolyorthoester and the number of hydrolyzable bonds in thepolyorthoester. Other factors determining the rate of release of anactive agent from the present pharmaceutical composition includeparticle size, solubility of the active agent, acidity of the medium(either internal or external to the matrix) and physical and chemicalproperties of the active agent in the matrix.

“Delivery vehicle” denotes a composition which has the functionsincluding transporting an active agent to a site of interest,controlling the rate of access to, or release of, the active agent bysequestration or other means, and facilitating the application of theagent to the region where its activity is needed.

“Matrix” denotes the physical structure of the polyorthoester ordelivery vehicle which essentially retains the active agent in a mannerpreventing release of the agent until the polyorthoester erodes ordecomposes.

“Polyorthoester-compatible” refers to the properties of an excipientwhich, when mixed with the polyorthoester, forms a single phase and doesnot cause any physical or chemical changes to the polyorthoester.

“Pro-drug” denotes a pharmacologically inactive or less active form of acompound which must be changed or metabolized in vivo, e.g., bybiological fluids or enzymes, by a subject after administration into apharmacologically active or more active form of the compound in order toproduce the desired pharmacological effect. Prodrugs of a compound canbe prepared by modifying one or more functional group(s) present in thecompound in such a way that the modification(s) may be cleaved in vivoto release the parent compound. Prodrugs include compounds wherein ahydroxy, amino, sulfhydryl, carboxy or carbonyl group in a compound isbonded to any group that can be cleaved in vivo to regenerate the freehydroxyl, amino, sulfhydryl, carboxy or carbonyl group respectively.Examples of prodrugs include, but are not limited to, esters (e.g.acetate, dialkylaminoacetates, formates, phosphates, sulfates andbenzoate derivatives) and carbamates of hydroxy functional groups (e.g.N,N-dimethylcarbonyl), esters of carboxyl functional groups (e.g. ethylesters, morpholinoethanol esters), N-acyl derivatives (e.g. N-acetyl),N-Mannich bases, Schiff bases and enaminones of amino functional groups,oximes, acetals, ketals, and enol esters of ketones and aldehydefunctional groups in a compound, and the like.

“Semi-solid” denotes the mechano-physical state of a material that isflowable under moderate stress. More specifically, the semi-solidmaterial should have a viscosity between about 10,000 and 3,000,000 cps,especially between about 50,000 and 500,000 cps. Preferably theformulation is easily syringable or injectable, meaning that it canreadily be dispensed from a conventional tube of the kind well known fortopical or ophthalmic formulations, from a needleless syringe, or from asyringe with a 16 gauge or smaller needle, such as 16-25 gauge.

“Sequestration” is the confinement or retention of an active agentwithin the internal spaces of a polyorthoester matrix. Sequestration ofan active agent within the matrix may limit the toxic effect of theagent, prolong the time of action of the agent in a controlled manner,permit the release of the agent in a precisely defined location in anorganism, or protect unstable agents against the action of theenvironment.

A “therapeutically effective amount” means the amount that, whenadministered to an animal for treating a disease, is sufficient toeffect treatment for that disease.

“Treating” or “treatment” of a disease includes treating the disease inan animal that may be predisposed to the disease but does not yetexperience or exhibit symptoms of the disease (prophylactic treatment),inhibiting the disease (slowing or arresting its development), providingrelief from the symptoms or side-effects of the disease (includingpalliative treatment), and relieving the disease (causing regression ofthe disease). For the purposes of this invention, a “disease” includespain.

A “unit” denotes an individual segment of a polyorthoester chain, whichconsists of the residue of a diketene acetal molecule and the residue ofa polyol.

An “α-hydroxy acid containing” unit denotes a unit where A is R¹, i.e.in which the polyol is prepared from an α-hydroxy acid or cyclic diesterthereof and a diol of the formula HO—R⁵—OH. The fraction of thepolyorthoester that is α-hydroxy acid containing units affects the rateof hydrolysis (or bioerodibility) of the polyorthoester, and in turn,the release rate of the active agent.

Polyorthoesters

The polyorthoesters are of formula I or formula II:

where:R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;R* is a C₁₋₄ alkyl;n is an integer of at least 5; andA is R¹, R², R³, or R⁴, where

R¹ is:

where:p is an integer of 1 to 20;R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:s is an integer of 0 to 30;t is an integer of 2 to 200; andR⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:x is an integer of 0 to 30;y is an integer of 2 to 200;R⁸ is hydrogen or C₁₋₄ alkyl;R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; and R⁴ is a the residue of a diolcontaining at least one functional group independently selected fromamide, imide, urea, and urethane groups;in which at least 0.01 mol % of the A units are of the formula R¹.

The structure of the polyorthoester useful for the present invention, asshown in formula I and formula II, is one of alternating residues of adiketene acetal and a diol, with each adjacent pair of diketene acetalresidues being separated by the residue of one polyol, preferably adiol.

In the presence of water, the α-hydroxy acid containing units arereadily hydrolyzed at a body temperature of 37° C. and a physiologicalpH, to produce the corresponding hydroxyacids. These hydroxyacids thenact as acidic catalysts to control the hydrolysis rate of thepolyorthoester without the addition of exogenous acid. When thepolyorthoester is used as a delivery vehicle or matrix entrapping anactive agent, the hydrolysis of the polyorthoester causes release of theactive agent.

Polyorthoesters having a higher mole percentage of the “α-hydroxy acidcontaining” units will have a higher rate of bioerodibility. Preferredpolyorthoesters are those in which the mole percentage of the “α-hydroxyacid containing” units is at least 0.01 mole percent, in the range ofabout 0.01 to about 50 mole percent, more preferably from about 0.05 toabout 30 mole percent, for example from about 0.1 to about 25 molepercent, especially from about 1 to about 20 mole percent. The molepercentage of the “α-hydroxy acid containing” units appropriate toachieve the desired composition will vary from formulation toformulation.

Preferred polyorthoesters are those where:

n is an integer of 5 to 1000;

the polyorthoester has a molecular weight of 1000 to 20,000, preferably1000 to 10,000, more preferably 1000 to 8000;

R⁵ is hydrogen or methyl;

R⁶ is:

where s is an integer of 0 to 10, especially 1 to 4; t is an integer of2 to 30, especially 2 to 10; and R⁷ is hydrogen or methyl;

R³ is:

where x is an integer of 0 to 10, especially 1 to 4; y is an integer of2 to 30, especially 2 to 10; and R⁸ is hydrogen or methyl;

R⁴ is selected from the residue of an aliphatic diol of 2 to 20 carbonatoms, preferably 2 to 10 carbon atoms, interrupted by one or two amide,imide, urea, or urethane groups;

the proportion of units in which A is R¹ is about 0.01-50 mol %,preferably 0.05-30 mol %, more preferably 0.1-25 mol %;

the proportion of units in which A is R² is less than 20%, preferablyless than 10%, especially less than 5%, and the proportion of units inwhich A is R⁴ is less than 20%, preferably less than 10%, especiallyless than 5%.

While the presence of any of these preferences results in apolyorthoester that is more preferred than the same polyorthoester inwhich the preference is not met, the preferences are generallyindependent, and polyorthoesters in which a greater number ofpreferences is met will generally result in a polyorthoester that ismore preferred than that in which a lesser number of preferences is met.

Preparation of the Polyorthoesters

The polyorthoesters are prepared according to the methods described inU.S. Pat. Nos. 4,549,010 and 5,968,543. Specifically, thepolyorthoesters are prepared by the reaction of a diketene acetal offormula III or formula IV:

where L is hydrogen or a C₁₋₃ alkyl,with a dial of the formula HO—R¹—OH and at least one dial of theformulae HO—R²—OH, HO—R³—OH, or HO—R⁴-0H.

To form the polyorthoester using a mixture of the two types of thedials, the mixture is formed with selected proportions based on thedesired characteristics of the polyorthoester. The use of increasingamounts of dials in which A is R¹ increases the bioerodibility of thepolyorthoester, and the use of such dials in which R⁶ is apolyethyleneoxide moiety or an alkane increases the softness of thepolymer; the use of increasing amounts of diols in which A is R²increases the hardness of the polyorthoester (and is therefore notgenerally desirable, though it may be useful in special circumstances);and the use of dials in which A is R³ increases the softness of thepolyorthoester, especially when these dials are low molecular weightpolyethylene glycols or aliphatic dials. The use of diols in which A isR⁴ also generally increases the hardness of the polyorthoester becauseof the hydrogen bonding between adjacent chains of the polyorthoester,and may or may not be desirable depending on the other dials used.

The preparation of the diketene acetals of the types of formula III andformula IV is disclosed in U.S. Pat. Nos. 4,304,767, 4,532,335, and5,968,543; and will be known to a person of ordinary skill in the art. Atypical method is the condensation of a bis(diol) of formula V (i.e.pentaerythritol) or formula VI:

with two equivalents of a 2-halocarboxaldehyde dialkyl acetal, such as2-bromoacetaldehyde diethyl acetal, followed by dehydrohalogenation togive the diketene acetal. The condensation of a glycol withdiethylbromoacetals is described in Roberts et al., J. Am. Chem. Soc.,80, 1247-1254 (1958), and dehydrohalogenation is described in Beyerstedtet al., J. Am. Chem. Soc., 58, 529-553 (1936).

The diketene acetals may also be prepared by the isomerization ofdivinyl acetals. Thus, for example,3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU) may beprepared by the isomerization of3,9-divinyl-2,4,8,10-tetraoxaspiro[5.5]undecane, using n-butyllithium inethylenediamine. The isomerization of the double bond is described inCorey et al., J. Org. Chem., 38, 3224 (1973). The divinyl acetals may beprepared by the condensation of the bis(diol) of formula V or formula VIwith two equivalents of a vinylic aldehyde, such as acrolein orcrotonaldehyde, or their dialkyl acetals, such as acrolein dimethylacetal, and such condensation reactions are well known.

The bis(diol) of formula VI where R is a bond is erythritol. Thehis(diol) of formula VI where R is —(CH₂)_(a)— may be prepared by theoxidation of an α,ω-diene, such as 1,3-butadiene or 1,5-hexadiene, withan oxidizing reagent such as osmium tetroxide/hydrogen peroxide, or byother methods known in the art, to give the bis(diol). The bis(diol) offormula VI where R is —(CH₂)_(b)—O—(CH₂)_(c)— may be prepared by thereaction of an w-hydroxy-α-olefin, such as allyl alcohol, with anω-haloalkyloxirane, such as epichlorohydrin, to form an ω-epoxy-α-olefinwith the backbone interrupted by an oxygen atom, such as2-allyloxymethyloxirane, which is then oxidized with an oxidizingreagent such as osmium tetroxide/hydrogen peroxide, or by other methodsknown in the art, to give the bis(diol).

The diols of the formulae HO—R¹—OH, HO—R²—OH, HO—R₃—OH, and HO—R⁴—OH areprepared according to methods known in the art, and as described, forexample, in U.S. Pat. Nos. 4,549,010 and 5,968,543. Some of the diolsare commercially available. The diol of the formula HO—R₁—OH thatcomprises a polyester moiety may be prepared by reacting a diol of theformula HO—R₆—OH with between 0.5 and 10 molar equivalents of a cyclicdiester of an α-hydroxy acid, such as lactide or glycolide, and allowingthe reaction to proceed at 100-200° C. for about 12 hours to about 48hours. Although particular solvents are not required for this reaction,organic solvents such as dimethylacetamide, dimethyl sulfoxide,dimethylformamide, acetonitrile, pyrrolidone, tetrahydrofuran, andmethylbutyl ether may be used. The preparation of diols, in particularthe diol of the formula HO—R₃—OH is generally disclosed in Heller etal., J. Polymer Sci., Polymer Letters Ed. 18:293-297 (1980), by reactingan appropriate divinyl ether with an excess of an appropriate diol.Diols of the formula HO—R₄—OH include diols where R₄ is R′CONR″R′(amide), R′CONR″COR′ (imide), R′NR″CONR″R′ (urea), and R′OCONR″R′(urethane), where each R′ is independently an aliphatic, aromatic, oraromatic/aliphatic straight or branched chain hydrocarbyl, especially astraight or branched chain alkyl of 2 to 22 carbon atoms, especially 2to 10 carbon atoms, and more especially 2 to 5 carbon atoms, and R″ ishydrogen or C₁₋₆ alkyl, especially hydrogen or methyl, more especiallyhydrogen. Some representative diols of the formula HO—R₄—OH includeN,N′-bis-(2-hydroxyethyl)-terephthalamide,N,N′-bis-(2-hydroxyethyl)pyromellitic diimide,1,1′-methylenedi(p-phenylene)-bis-[3-(2-hydroxyethyl)urea],N,N′-bis-(2-hydroxyethyl)oxamide, 1,3-bis(2-hydroxyethyl)urea,3-hydroxy-N-(2-hydroxyethyl)propionamide,4-hydroxy-N-(3-hydroxypropyl)butyramide, andbis(2-hydroxyethyl)ethylenedicarbamate. These diols are known to the artin reported syntheses and may are commercially available. Representativediols of the formula HO—(CH₂)_(n)—NHCO—(CH₂)_(m)OH where n is an integerof 2 to 6 and m is an integer of 2 to 5 are made by the reaction of2-aminoethanol, 3-aminopropanol, 4-aminobutanol, 5-aminopentanol, or6-aminohexanol with β-propiolactone, γ-butyrolactone, 6-valerolactone,or F-caprolactone. Representative diols of the formulaHO—(CH₂)_(n)—NHCOO—(CH₂)_(m)OH where n and m are each integers of 2 to 6are made by the reaction of the same aminoalcohols just mentioned withcyclic carbonates of the formula

such as ethylene carbonate. Bis-amide diols of the formulaHO-A-NHCO—B—CONH-A-OH are prepared by the reaction of a diacid,optionally in activated form, such as the diacyldihalide, with twoequivalents of a hydroxy-amine. Other methods of preparation of thediols of the formula HO—R⁴—OH are known in the art.

Once made, the diol of the formula HO—R¹—OH and the diol(s) of theformulae HO—R²—OH, HO—R³—OH, and HO—R⁴—OH in the desired proportions aremixed with the diketene acetal of formula III or formula IV, in aslightly less than 1:1 (e.g. 0.5:1-0.9:1) ratio of total number of molesof diketene acetal to total number of moles of diols, in a suitablesolvent at ambient temperature. The condensation reaction between thediketene acetal and the diols is carried out under conditions which aredescribed in, for example, U.S. Pat. Nos. 4,304,767, 4,549,010, and5,968,543, and are well known to those skilled in the art; and will alsobe readily apparent from the structures of the reactants themselves.Suitable solvents are aprotic solvents, such as dimethylacetamide,dimethyl sulfoxide, dimethylformamide, acetonitrile, acetone, ethylacetate, pyrrolidone, tetrahydrofuran, and methylbutyl ether, and thelike. Catalysts are not required for this reaction, but when used,suitable catalysts are iodine in pyridine, p-toluenesulfonic acid;salicylic acid, Lewis acids (such as boron trichloride, borontrifluoride, boron trichloride etherate, boron trifluoride etherate,stannic oxychloride, phosphorous oxychloride, zinc chloride, phosphoruspentachloride, antimony pentafluoride, stannous octoate, stannicchloride, diethyl zinc, and mixtures thereof); and Brønsted catalysts(such as polyphosphoric acid, crosslinked polystyrene sulfonic acid,acidic silica gel, and mixtures thereof). A typical amount of catalystused is about 0.2% by weight relative to the diketene acetal. Smaller orlarger amounts can also be used, such as 0.005% to about 2.0% by weightrelative to the diketene acetal. Once the reaction is complete, thereaction mixture is allowed to cool and concentrated by rotoevaporationunder vacuum. The concentrated mixture may be further dried under vacuumat an elevated temperature.

The polyorthoesters may also be prepared by reaction of the diketeneacetal with the chosen diol(s) under similar reaction conditions, but inthe presence of a “chain stopper” (a reagent that terminatespolyorthoester chain formation). Suitable chain stoppers are C₅₋₂₀alkanols, especially C₁₀₋₂₀ alkanols. The chain stopper is preferablypresent in from 1-20 mol % based on the diketene acetal. Thepolyorthoesters thus prepared have low molecular weights with a lowermolecular weight dispersion than those prepared by the reaction of thediketene acetals with only diols, and are therefore especially suitablefor this invention.

The Excipients

The excipients suitable for the present invention are pharmaceuticallyacceptable and polyorthoester-compatible materials. They are liquid atroom temperature, and are readily miscible with the polyorthoesters.

Suitable excipients include poly(ethylene glycol) ether derivativeshaving a molecular weight of between 200 and 4,000, such aspoly(ethylene glycol) mono- or di-alkyl ethers, preferably poly(ethyleneglycol)monomethyl ether 550 or poly(ethylene glycol)dimethyl ether 250;poly(ethylene glycol)copolymers having a molecular weight of between 400and 4,000 such as poly(ethylene glycol-co-polypropylene glycol);propylene glycol mono- or di-esters of a C₂₋₁₉ aliphatic carboxylic acidor a mixture of such acids, such as propylene glycol dicaprylate ordicaprate; mono-, di- or tri-glycerides of a C₂₋₁₉ aliphatic carboxylicacid or a mixture of such acids, such as glyceryl caprylate, glycerylcaprate, glyceryl caprylate/caprate, glyceryl caprylate/caprate/laurate,glycofurol and similar ethoxylated tetrahydrofurfuryl alcohols and theirC₁₋₄ alkyl ethers and C₂₋₁₉ aliphatic carboxylic acid esters; andbiocompatible oils such as sunflower oil, sesame oil and other non- orpartially-hydrogenated vegetable oils.

Most of these materials are commercially available, for example, fromAldrich Chemical Company (Milwaukee, Wis.) and from Abitec Corporation(Columbus, Ohio), LIPO Chemicals Inc. (Paterson, N.J.), and JarchemIndustries, Inc. (Newark, N.J.).

The Delivery Vehicle

The delivery vehicle comprises a polyorthoester and an excipientselected from those described in preceding sections.

The concentrations of the polyorthoester and the excipient in thedelivery vehicle may vary. For example, the concentration of theexcipient in the vehicle may be in the range of 1-99% by weight,preferably 5-80% weight, especially 20-60% by weight of the vehicle.

While the singular form is used to describe the polyorthoester andexcipient in this application, it is understood that more than onepolyorthoesters and excipients selected from the groups described abovemay be used in the delivery vehicle.

The delivery vehicle is prepared by mixing or blending together thepolyorthoester and the excipient. The mixing or blending can beperformed by any methods at a temperature less than about 50° C., e.g.at room temperature, in the absence of solvents, using any suitabledevices to achieve a homogeneous, flowable and non-tacky semi-solidblend at room temperature. In another aspect of the invention, themixing or blending can be performed by any methods at a temperature ofabout between 5 to 200° C., more preferably about between 20 to 150° C.,and more preferably about between 25 and 100° C., depending on thenature of the starting material selected, as noted above, to achieve ahomogeneous, flowable and tacky or non-tacky semi-solid blend at roomtemperature.

Semi-Solid Pharmaceutical Compositions

If the active agent is itself a liquid or semi-solid, it may be mixedwith the delivery vehicle in the same manner as the delivery vehicle wasformed, i.e. conventional blending of semi-solid formulations. Suchblending is carried out in a manner suitable to obtain a homogeneousdistribution of the components throughout the formulation, by mixing thecomponents in any order necessary to achieve such homogeneity. However,the active agent is typically a solid. It is desirable that the particlesize of the active agent be sufficiently small (for example, 1-100 μm,especially 5-50 μm) so that the resulting composition is smooth.Therefore, unless the active agent is already in micron-sized powderform, it is generally first milled into fine particles preferably lessthan 100 μm and sieved before mixing with the other ingredients. Themechanical mixing process is performed at room temperature, preferablyunder vacuum in order to avoid air bubbles. In another aspect of theprocess, the mechanical mixing process may be performed at roomtemperature or above room temperature without the use of any vacuum. Ifdesired, further size reduction of the size of the particles of theactive agent can be carried out by passing the semi-solid mixturethrough a ball mill or roller mill to achieve a homogeneous and uniformpharmaceutical composition.

The active agent may be mixed with the delivery vehicle already formedor directly mixed together with the polyorthoester and the excipient. Inanother aspect of the invention, the active agent, delivery vehicle,polyorthoester and excipient may be mixed together in any suitable orderto obtain the product which is homogeneous and with the desiredcharacteristics.

The active agent is present in the composition in an amount which iseffective to provide a desired biological or therapeutic effect. Becauseof the sustained release nature of the compositions, the active agentusually is present in an amount which is greater than the conventionalsingle dose. The concentration of the active agent in the semi-solidpolyorthoester composition can vary over a wide range (e.g., 0.1-80 wt.%, preferably 0.3-60 wt. %, more preferably 0.5-40 wt. %, such as 1-30wt. %, based on the composition as a whole) depending on a variety offactors, such as the release profile of the composition, thetherapeutically effective dose of the active agent, and the desiredlength of the time period during which the active agent is released. Inone aspect of the invention, the concentration of the active agent inthe semi-solid polyorthoester composition is between about 1-5 wt. %,more preferably between about 2-3 wt. %.

The concentration of the polyorthoester may be 1-99 wt. %, preferably5-40 wt. %, of the composition. The total concentration of the excipientis 1-90 wt. %, preferably 5-60 wt. %, more preferably 10-50 wt. %, ofthe composition.

It is also understood that while not required, other pharmaceuticallyacceptable inert agents such as coloring agents and preservatives mayalso be incorporated into the composition.

The semi-solid pharmaceutical composition of the present invention hasan improved texture which is non-tacky and flowable. In another aspectof the invention, the semi-solid pharmaceutical composition of thepresent invention has an improved texture which is tacky and alsoflowable. As used herein, the term “tacky” refers to a physical propertyof the composition in which the composition is sticky when lightlytouched. The composition therefore can be conveniently applied to theskin or mucous membrane in the manner of a convention al cream or gel.Preferably the formulation is easily syringable or injectable, meaningthat it can readily be dispensed from a conventional tube of the kindwell known for topical or ophthalmic formulations, from a needlelesssyringe, or from a syringe with a 16 gauge or smaller needle (such as16-25 gauge), and injected subcutaneously, intradermally orintramuscularly. The formulation may be applied using various methodsknown in the art, including by syringe, injectable or tube dispenser,for example, directly or indirectly to the skin or a wound.

After topical application, administration by injection, or any otherroutes of administration, including surface or subcutaneous applicationto open wounds, the active agent is released from the composition in asustained and controlled manner. The rate of release may be regulated orcontrolled in a variety of ways to accommodate the desired therapeuticeffect. The rate may be increased or decreased by altering the molepercentage of the α-hydroxy acid containing units in the polyorthoester,or by selecting a particular excipient, or by altering the amount of theselected excipient, or the combination thereof.

The compositions are also stable. The release rates of the active agentare not affected by irradiation for sterilization.

Particular Compositions and their Uses

Exemplary compositions of this invention, and their uses, include:

(1) compositions containing local anesthetics, optionally in combinationwith glucocorticosteroids such as dexamethasone, cortisone,hydrocortisone, prednisone, prednisolone, beclomethasone, betamethasone,flunisolide, fluocinolone acetonide, fluocinonide, triamcinolone,including deposition of the compositions into surgical sites, and thelike, for the prolonged relief of local pain or a prolonged nerveblockade. This use is discussed further below;(2) compositions containing cancer chemotherapeutic agents, such asthose listed above under “Active Agents”, for deposition by syringe orby injection into tumors or operative sites from which a tumor has beenablated, for tumor control or treatment and/or the suppression ofregrowth of the tumor from residual tumor cells after ablation of thetumor;(3) compositions containing progestogens, such as flurogestone,medroxyprogesterone, norgestrel, norgestimate, norethindrone, and thelike, for estrus synchronization or contraception;(4) compositions containing antimetabolites such as fluorouracil and thelike, as an adjunct to glaucoma filtering surgery; compositionscontaining antiangiogenic agents such as combrestatin, for the treatmentof macular degeneration and retinal angiogenesis; and other compositionsfor the controlled release of ophthalmic drugs to the eye;(5) compositions containing therapeutic polypeptides (proteins), such asinsulin, LHRH antagonists, and the like, for the controlled delivery ofthese polypeptides, avoiding the need for daily or other frequentinjection;(6) compositions containing anti-inflammatory agents such as the NSAIDs,e.g. ibuprofen, naproxen, COX-1 or COX-2 inhibitors, and the like, orglucocorticosteroids, for intra-articular application or injection;(7) compositions containing antibiotics, for the prevention or treatmentof infection, especially for deposition into surgical sites to suppresspost-operative infection, or into or on wounds, for the suppression ofinfection (e.g. from foreign bodies in the wound);(8) compositions containing morphogenic proteins such as bonemorphogenic protein;(9) compositions containing DNA or other polynucleotides, such asantisense oligonucleotides;(10) compositions containing antiemetic agents;(11) compositions containing antigens in vaccines; and(12) compositions comprising a combination of two or more of the aboveactive agents for concurrent therapeutic applications.

Delivery of Controlled-Release Antiemetic Agents

The present invention further relates to a method for the treatment orprevention of emesis in a patient which comprises administering an 5-HT₃antagonist, wherein the 5-HT₃ antagonist minimize the side effects ofnausea and/or emesis associated with other pharmacological agents.

In a further aspect of the present invention, there is provided apharmaceutical composition for the treatment or prevention of emesiscomprising an HT₃ antagonist, together with at least onepharmaceutically acceptable carrier or excipient.

As used herein, the term “emesis” include nausea and vomiting. The HT₃antagonists in the semi-solid injectable form of the present inventionare beneficial in the therapy of acute, delayed or anticipatory emesis,including emesis induced by chemotherapy, radiation, toxins, viral orbacterial infections, pregnancy, vestibular disorders (e.g. motionsickness, vertigo, dizziness and Meniere's disease), surgery, migraine,and variations in intracranial pressure. The HT₃ antagonist of use inthe invention are of particular benefit in the therapy of emesis inducedby radiation and/or by chemotherapy, for example during the treatment ofcancer, or radiation sickness; and in the treatment of post-operativenausea and vomiting. The HT₃ antagonists in the semi-solid injectableform of the invention are beneficial in the therapy of emesis induced byantineoplastic (cytotoxic) agents including those routinely used incancer chemotherapy, and emesis induced by other pharmacological agents,for example, alpha-2 adrenoceptor antagonists, such as yohimbine, MK-912and MK-467, and type IV cyclic nucleotide phosphodiesterase (PDE4)inhibitors, such as RS14203, CT-2450 and rolipram.

Particular examples of chemotherapeutic agents are described, forexample, by D. J. Stewart in Nausea and Vomiting: Recent Research andClinical Advances, ed. J. Kucharczyk et al., CRC Press Inc., Boca Raton,Fla., USA, 1991, pages 177-203, see page 188. Examples of commonly usedchemotherapeutic agents include cisplatin, dacarbazine (DTIC),dactinomycin, mechlorethamine (nitrogen mustard), streptozocin,cyclophosphamide, carmustine (BCNU), lomustine (CCNU), doxorubicin(adriamycin), daunorubicin, procarbazine, mitomycin, cytarabine,etoposide, methotrexate, 5-fluorouracil, vinblastine, vincristine,bleomycin and chlorambucil (see R. J. Gralle et al. in Cancer TreatmentReports, 1984, 68, 163-172).

Many of the antiemetic agents are conventionally used in the form oftheir acid addition salts, as this provides solubility in aqueousinjection media. However, because the presence of the large amount ofacid within such a local antiemetic acid addition salt will result inmore rapid degradation of the polyorthoesters and rapid release of theantiemetic agent, it is generally desirable to use the antiemetic agentin the free base form. Alternatively, the antiemetic may be used withonly a small proportion of the acid addition salt present (addition ofsmall quantities of the acid addition salt may provide enhanced releaseif desired).

The semi-solid injectable form of an antiemetic agent of the presentinvention is prepared by incorporating the antiemetic agent into thedelivery vehicle in a manner as described above. The concentration ofthe antiemetic agent may vary from about 0.1-80 wt. %, preferably fromabout 0.2-60 wt. %, more preferably from about 0.5-40 wt. %, mostpreferably from about 1-5 wt. %, for example, about 2-3 wt. %. Thesemi-solid composition is then filled into a syringe with a 16-25 gaugeneedle, and injected into sites that have been determined to be mosteffective. The semi-solid injectable composition of the presentinvention can be used for controlled delivery of both slightly solubleand soluble antiemetic agents.

Suitable classes of antiemetic agents employed in the present inventioninclude, for example, a 5-HT₃ antagonist such as ondansetron,granisetron or tropisetron; a dopamine antagonist such as metoclopramideor domperidone; an anticholinergic agent such as scopolamine; a GABA_(B)receptor agonist such as baclofen; an NK₁ receptor antagonist asdescribed, for example, in WO 97/49710; or a GABA_(A)α₂ and/or asreceptor agonist as described in WO 99/67245.

The 5-HT₃ antagonists employed in the present invention are also usefulfor the treatment of or prevention of emesis in conjunction with the useof other antiemetic agents known in the art.

In one particular aspect, suitable classes of other antiemetic agents ofuse in conjunction with the present invention include, for example,alpha-2 adrenoreceptor agonists including for example, clonidine,apraclonidine, para-aminoclonidine, brimonidine, naphazoline,oxymetazoline, tetrahydrozoline, tramazoline, detomidine, medetomidine,dexmedetomidine, B-HT 920, B-HIT 933, xylazine, rilmenidine, guanabenz,guanfacine, labetalol, phenylephrine, mephentermine, metaraminol,methoxamine and xylazine.

As noted, the compounds or agents employed in the present invention arealso useful for the treatment of or prevention of emesis in conjunctionwith another antiemetic agents known in the art, such as a 5-HT₃antagonist, a dopamine antagonist, an anticholinergic agent, a GABA_(B)receptor agonist, an NK₁ receptor antagonist, and a GABA_(A)α₂ and/or asreceptor agonist.

In another aspect of the invention, the antiemetic agents as a singleagent or as a combination, may be used independently in the form of asalt or salts or mixtures of the agent and the salt of the agent.Suitable pharmaceutically acceptable salts of the compounds of use inthe present invention include acid addition salts which may, forexample, be formed by mixing a solution of the compound with a solutionof a pharmaceutically acceptable non-toxic acid such as hydrochloricacid, iodic acid, fumaric acid, maleic acid, succinic acid, acetic acid,citric acid, tartaric acid, carbonic acid, phosphoric acid, sulfuricacid and the like. Salts of amine groups may also comprise thequaternary ammonium salts in which the amino nitrogen atom carries analkyl, alkenyl, alkynyl or aralkyl group. Where the compound carries anacidic group, for example a carboxylic acid group, the present inventionalso contemplates salts thereof, preferably non-toxic pharmaceuticallyacceptable salts thereof, such as the sodium, potassium and calciumsalts thereof.

It will be appreciated that when using a combination of the presentinvention, the 5-HT₃ antagonists and the other antiemetic agent will beadministered to a patient together in the semi-solid injectable form ofthe invention. In one aspect of the invention, the compounds may be inthe same pharmaceutically acceptable carrier and therefore administeredsimultaneously.

When administered in combination, either as a single product in thesemi-solid injectable form or as separate pharmaceutical compositions,the 5-HT₃ antagonists and the other antiemetic medicament are to bepresented in a ratio which is consistent with the manifestation of thedesired effect. In particular, the ratio by weight of the 5-HT₃antagonists and the other antiemetic agent will suitably be between0.001 to 1 and 1000 to 1, and especially between 0.01 to 1 and 100 to 1.

The present invention is further directed to a method for amelioratingthe symptoms attendant to emesis in a patient comprising administeringto the patient an 5-HT₃ antagonists. In accordance with the presentinvention the 5-HT₃ antagonists is administered to a patient in aquantity sufficient to treat or prevent the symptoms and/or underlyingetiology associated with emesis in the patient.

Delivery of Controlled-Release Local Anesthetics

Local anesthetics induce a temporary nerve conduction block and providepain relief which lasts from a few minutes to a few hours. They arefrequently used to prevent pain in surgical procedures, dentalmanipulations or injuries.

The synthetic local anesthetics may be divided into two groups: theslightly soluble compounds and the soluble compounds. Conventionally,the soluble local anesthetics can be applied topically and by injection,and the slightly soluble local anesthetics are used only for surfaceapplication. The local anesthetics conventionally administered byinjection can also be divided into two groups, esters and non-esters.The esters include (1) benzoic acid esters (piperocaine, meprylcaine andisobucaine); (2) para-aminobenzoic acid esters (procaine, tetracaine,butethamine, propoxycaine, chloroprocaine); (3) meta-aminobenzoic acidesters (metabutethamine, primacaine); and (4) para-ethoxybenzoic acidester (parethoxycaine). The non-esters are anilides (amides ornonesters) which include bupivacaine, lidocaine, mepivacaine, pyrrocaineand prilocaine.

Many of the local anesthetics are conventionally used in the form oftheir acid addition salts, as this provides solubility in aqueousinjection media. However, because the presence of the large amount ofacid within such a local anesthetic acid addition salt will result inmore rapid degradation of the polyorthoesters and release of the localanesthetic, it is generally desirable to use the local anesthetics infree base form, or with only a small proportion of the acid additionsalt present (addition of small quantities of the acid addition salt mayprovide enhanced release if desired).

The semi-solid injectable form of a local anesthetic of the presentinvention is prepared by incorporating the local anesthetic into thedelivery vehicle in a manner as described above. The concentration ofthe local anesthetic may vary from about 0.1-80 wt. %, preferably fromabout 1-60 wt. %, more preferably from about 0.5-40 wt. %, mostpreferably from about 1-5 wt. %, for example, about 2-3 wt. %. Thesemi-solid composition can be administered directly into surgicalincision sites or sub-cutaneously via a suitable sized needle. Inanother aspect, the semi-solid composition is then filled into a syringewith a 16-25 gauge needle, and injected into sites that are painful orto be subjected to surgical procedures. The semi-solid injectablecomposition of the present invention can be used for controlled deliveryof both slightly soluble and soluble local anesthetics.

Because the duration of action of a local anesthetic is proportional tothe time during which it is in actual contact with nervous tissues, thepresent injectable delivery system can maintain localization of theanesthetic at the nerve for an extended period of time which willgreatly prolong the effect of the anesthetic.

A number of authors, including Berde et al., U.S. Pat. No. 6,046,187 andrelated patents, have suggested that the co-administration of aglucocorticosteroid may prolong or otherwise enhance the effect of localanesthetics, especially controlled-release local anesthetics; andformulations containing a local anesthetic and a glucocorticosteroid,and their uses for controlled release local anesthesia, are within thescope of this invention.

ASPECTS OF THE INVENTION

In one aspect of the invention, there is provided a pharmaceuticalcomposition comprising:

(A) semi-solid delivery vehicle, comprising:

-   -   (i) a polyorthoester of formula I or formula II:

where:R is a bond, —(CH₂)_(a)—, or —(CH₂)_(b)—O—(CH₂)_(c)—; where a is aninteger of 1 to 10, and b and c are independently integers of 1 to 5;R* is a C₁₋₄ alkyl;n is an integer of at least 5; andA is R¹, R², R³, or R⁴, where

R¹ is:

where:p is an integer of 1 to 20;R⁵ is hydrogen or C₁₋₄ alkyl; and

R⁶ is:

where:s is an integer of 0 to 30;t is an integer of 2 to 200; andR⁷ is hydrogen or C₁₋₄ alkyl;

R² is:

R³ is:

where:x is an integer of 0 to 30;y is an integer of 2 to 200;R⁸ is hydrogen or C₁₋₄ alkyl;R⁹ and R¹⁰ are independently C₁₋₁₂ alkylene;R¹¹ is hydrogen or C₁₋₆ alkyl and R¹² is C₁₋₆ alkyl; or R¹¹ and R¹²together are C₃₋₁₀ alkylene; andR⁴ is the residue of a diol containing at least one functional groupindependently selected from amide, imide, urea, and urethane groups;in which at least 0.01 mol percent of the A units are of the formula R¹;and

-   -   (ii) a pharmaceutically acceptable, polyorthoester-compatible        liquid excipient selected from polyethylene glycol ether        derivatives having a molecular weight between 200 and 4000,        polyethylene glycol copolymers having a molecular weight between        400 and 4000, mono-, di-, or tri-glycerides of a C₂₋₁₉ aliphatic        carboxylic acid or a mixture of such acids, alkoxylated        tetrahydrofurfuryl alcohols and their C₁₋₄ alkyl ethers and        C₂₋₁₉ aliphatic carboxylic acid esters, and biocompatible oils;        and

(B) an antiemetic agent, and/or an anesthetic agent.

In another aspect of the invention, there is provided the semi-soliddelivery vehicle above where the concentration of the polyorthoesterranges from 1% to 99% by weight. In one variation, the polyorthoesterhas a molecular weight between 1,000 and 20,000. In another aspect, thefraction of the A units that are of the formula R¹ is between 1 and 90mol percent.

In one aspect of the invention, the polyorthoester is of formula I,where none of the units have A equal to R², R³ is:

where x is an integer of 0 to 10; y is an integer of 2 to 30; and R⁶ is:

where s is an integer of 0 to 10, t is an integer of 2 to 30, and R⁵,R⁷, and R⁸ are independently hydrogen or methyl. In one variation, R³and R⁶ are both —(CH₂—CH₂—O)₂—(CH₂—CH₂)—, R⁵ is methyl, and p is 1 or 2.In another variation, R³ and R⁶ are both —(CH₂—CH₂—O)₉—(CH₂—CH₂)—, R⁵ ismethyl, and p is 1 or 2.

In one aspect of the invention, there is provided a pharmaceuticalcomposition of wherein the anesthetic agent is selected from the groupconsisting of bupivacaine, lidocaine, mepivacaine, pyrrocaine andprilocaine. In one variation, the concentration of the anesthetic agentin the composition is about 1-5 wt. %.

In one aspect of the invention, there is provided the above compositionwherein the antiemetic agent is granisetron. In one variation, thefraction of the antiemetic agent is from 0.1% to 80% by weight of thecomposition. In another variation, the fraction of the antiemetic agentis from 1% to 5% by weight of the composition.

In another aspect of the invention, the composition is in topical,syringable, or injectable form.

In yet another aspect of the invention, there is provided a compositionwherein the antiemetic agent is selected from the group consisting of5-HT₃ antagonists, a dopamine antagonists, an anticholinergic agents, aGABA_(B) receptor agonists, an NK₁ receptor antagonists, and aGABA_(A)α₂ and/or as receptor agonists. In one variation, the antiemeticagent is a 5-HT₃ antagonist. In another variation, the 5-HT₃ antagonistis selected from the group consisting of ondansetron, granisetron andtropisetron.

In yet another aspect, there is provided the above pharmaceuticalcomposition further comprising a second antiemetic agent to form acombination composition. In one variation, the second antiemetic agentis selected from the group consisting of alpha-2 adrenoreceptoragonists, a dopamine antagonist, an anticholinergic agent, a GABA_(B)receptor agonist, an NK₁ receptor antagonist, and a GABA_(A)α₂ and/or asreceptor agonist. In another variation, the alpha-2 adrenoreceptoragonists is selected from the group consisting of clonidine,apraclonidine, para-aminoclonidine, brimonicline, naphazoline,oxymetazoline, tetrahydrozoline, tramazoline, detomidine, medetomidine,dexmedetomidine, B-HT 920, B-HIT 933, xylazine, rilmenidine, guanabenz,guanfacine, labetalol, phenylephrine, mephentermine, metaraminol,methoxamine and xylazine.

In another aspect of the invention, there is provided a method for thetreatment of emesis induced by a chemotherapeutic agent, byradiation-induced nausea and vomiting, and/or by post-operative inducednausea and vomiting in a patient in need thereof which comprisesadministering to the patient the above composition comprising the 5-HT₃antagonist of the invention. In one variation of the above method, the5-HT₃ antagonist is selected from the group consisting of ondansetron,granisetron and tropisetron. In another variation of the above method,the patient is a human. In yet another variation of the method, theadministration comprises the deposition of the 5-HT₃ antagonist into asurgical site.

In another aspect of the invention, there is provided a method for theprevention of emesis induced by a chemotherapeutic agent in a patient inneed thereof which comprises administering to the patient the abovecomposition comprising the 5-HT₃ antagonist. In one variation, the 5-HT₃antagonist is selected from the group consisting of ondansetron,granisetron and tropisetron. In another variation of the above method,the patient is a human.

In another aspect, there is provided a method for ameliorating thesymptoms attendant to emesis induced by a chemotherapeutic agent, byradiation-induced nausea and vomiting, and/or by post-operative inducednausea and vomiting in a patient comprising administering to the patientin need thereof a composition of the invention comprising an 5-HT₃antagonist. In one variation, the 5-HT₃ antagonist is selected from thegroup consisting of ondansetron, granisetron and tropisetron. In onevariation of the above method, the patient is a human.

In another aspect of the invention, there is provided a method for theprevention of emesis induced by a chemotherapeutic agent, byradiation-induced nausea and vomiting, and/or by post-operative inducednausea and vomiting in a patient in need thereof which comprisesadministering to the patient a composition of the invention comprising a5-HT₃ antagonist, and a second antiemetic agent. In one variation, thesecond antiemetic agent is a compound selected from the group consistingof alpha-2 adrenoreceptor agonists, a dopamine antagonist, ananticholinergic agent, a GABA_(B) receptor agonist, an NK₁ receptorantagonist, and a GABA_(A)α₂ and/or α₃ receptor agonist.

In yet another aspect of the invention, there is provided a process forthe preparation of the delivery vehicle of the present invention,comprising mixing the components (A) and (B) in the absence of asolvent, at a temperature between about 20 and 150° C.

In yet another aspect, there is provided a process for the preparationof the pharmaceutical composition above where the antiemetic agent is insolid form, comprising: (1) optionally milling the active agent toreduce the particle size of the active agent; (2) mixing the activeagent and the delivery vehicle; and (3) optionally milling thecomposition to reduce the particle size of the active agent.

In yet another aspect, there is provided a process for the preparationof the pharmaceutical composition of the present invention where theantiemetic agent and/or the anesthetic agent is in solid form,comprising: (1) warming the polyorthoester to 70° C.; (2) dissolving theactive agent in the excipient at 120-150° C.; and (3) mixing the 70° C.polyorthoester into the 120° C. solution of the active agent in theexcipient with an agitator under the following conditions to obtain ahomogeneous distribution of the components: (a) under an inertatmosphere, such as an argon or nitrogen atmosphere (b) optionallywarming the mixing vessel to 70° C.; or (c) optionally allowing thetemperature of the mixture to equilibrate under ambient conditionsduring the mixing process.

EXAMPLES Example 1 Preparation of Polyorthoesters

The following syntheses illustrate the preparation of representativepolyorthoesters. The starting materials are either commerciallyavailable or may be prepared as described in the preceding sections andin U.S. Pat. Nos. 4,549,010 and 5,968,543.

1(a) The polyorthoester in this example was prepared from3,9-di(ethylidene)-2,4,8,10-tetraoxaspiro[5.5]undecane (DETOSU),triethylene glycol (TEG), and triethyleneglycol monoglycolide (TEG-mGL).The molar ratio of the three components (DETOSU:TEG:TEG-mGL) was65:95:5.

Under rigorously anhydrous conditions, DETOSU (6.898 g, 32.5 mmol), TEG(7.133 g, 47.5 mmol) and TEG-mGL (0.521 g, 2.5 mmol) were weighed into a250 mL round bottom flask, and the mixture dissolved in anhydrous ethylacetate (16 mL). To this solution was added a salicylic acid solution inethyl acetate (12 drops, 10 mg/mL) to initiate the polymerization. Thesolution came to a boil within a few minutes. The solution was allowedto cool to room temperature, then concentrated by rotoevaporation at40-50° C. The flask was transferred to a vacuum oven, and dried at 40°C. for 2 hours followed by drying at 70° C. for additional 3 hours. Thematerial was semi-solid with a molecular weight of about 4000.

1(b) The polyorthoester in this example was prepared from DETOSU, TEG,and triethyleneglycol diglycolide (TEG-diGL). The molar ratio of thethree components (DETOSU:TEG:TEG-diGL) was 65:80:20. Following theprocedure of Example 1(a), DETOSU (6.898 g, 32.5 mmol), TEG (6.007 g, 40mmol) and TEG-diGL (2.662 g, 10 mmol) were allowed to react. Thereaction yielded a semi-solid material having a molecular weight ofabout 2000.

1(c) The polyorthoester in this example was prepared from DETOSU, TEG,and TEG-diGL. The molar ratio of the three components(DETOSU:TEG:TEG-diGL) was 60:70:30. Following the procedure of Example1(a), DETOSU (25.470 g, 120 mmol), TEG (21.024 g, 140 mmol) and TEG-diGL(15.973 g, 60 mmol) were allowed to react. The reaction yielded asemi-solid material having a molecular weight of about 2000.

Other polyorthoesters, e.g. those containing diketene acetals of formulaIV and/or those containing other diols of formulae HO—R¹—OH, HO—R²—OH,HO—R³—OH, and HO—R⁴—OH, are prepared by similar methods.

1(d) The polyorthoester in this example was prepared from DETOSU, TEOand TEG-diOL. The molar ratio of the three components(DETOSU:TEG:TEG-diOL) was 90:80:20. Under rigorously anhydrousconditions, DETOSU (114.61 g, 540 mmol) was dissolved in a 2 L flask in450 mL anhydrous THF and TEG (72.08 g, 480 mmol) and TEG-diGL (31.95 g,120 mmol) was weighed into a 500 mL round bottom flask, and dissolved inanhydrous THF (50 mL). The TEG-diGL solution was added to the solutionof DETOSU and TEG to initiate the polymerization. The solution came to aboil within a few minutes. The solution was allowed to cool to roomtemperature, then concentrated by rotary evaporation at 50° C., followedby rotary evaporation at 80° C. The material was semi-solid with amolecular weight of about 6,500.

Example 2 Preparation of Pharmaceutical Compositions

2(a) Semi-solid pharmaceutical compositions with bupivacaine as theactive agent were prepared by first milling the bupivacaine into fineparticles and sieving, before mixing with selected amounts of apolyorthoester and an excipient. The mixing process was performed atroom temperature under vacuum. Further size reduction of the bupivacaineparticles was carried out by passing the semi-solid composition througha ball mill.

-   A. 60 wt. % polyorthoester (DETOSU/TEG/TEG-mGL 60:95:5)    -   40 wt. % bupivacaine. (control)-   B. 40 wt. % polyorthoester (DETOSU/TEG/TEG-mGL 60:95:5)    -   40 wt. % bupivacaine    -   20 wt. % polyethylene glycol monomethyl ether 550.-   C. 60 wt. % polyorthoester (DETOSU/TEG/TEG-diGL 60:80:20)    -   40 wt. % bupivacaine. (control)-   D. 40 wt. % polyorthoester (DETOSU/TEG/TEG-diGL 60:80:20)    -   40 wt. % bupivacaine    -   20% wt. % polyethylene glycol monomethyl ether 550.-   E. 20% wt. % polyorthoester (DETOSU/TEG/TEG-diGL 60:70:30)    -   40% wt. % bupivacaine    -   40% wt. % polyethylene glycol monomethyl ether.

Compositions B, D, and E had non-tacky, flowable texture. Compositions Aand C had very sticky texture, were difficult to handle and showed poorsyringability.

2(b) Semi-solid pharmaceutical compositions with mepivacaine as theactive agent were prepared by dissolving the mepivacaine in theexcipient ether 550 at a temperature between 120° C. and 150° C. in onevessel and mixing in the specified amount of the polyorthoester that waspreviously warmed to 70° C. to make it flowable in a separate vessel.The formulation was additionally transferred once between the twovessels to ensure complete transfer of all components into a singlevessel, and further mixed under an argon or nitrogen environment. Thismixing may be carried out with or without warming the mixing vessel at70° C. in order to maintain the flow characteristics necessary for ahomogeneous distribution of all the components throughout theformulation. An example of a composition of such a formulation is shownbelow:

77.6 weight % polyorthoester (molar ratio ofDETOSU:TEG:TEG-diGL/90:80:20)

19.4 weight % polyethylene glycol monomethyl ether 550

3.0 weight % mepivacaine.

2(c) Semi-solid pharmaceutical compositions with granisetron as theactive agent were prepared as described in Example 2(b) to obtain thefollowing composition:

78.4 weight % polyorthoester (molar ratio ofDETOSU:TEG:TEG-diGL/90:80:20)

19.6 weight % polyethylene glycol monomethyl ether 550

2.0 weight % granisetron.

2(d) A semi-solid delivery vehicle was prepared in a manner similar tothat described in Example 2(b), with the omission of the step todissolve the active pharmaceutical ingredient in the excipient. Anexample of a composition of a semi-solid delivery vehicle is shownbelow:

80 weight % polyorthoester (molar ratio of DETOSU:TEG:TEG-diGL/90:80:20)

20 weight % polyethylene glycol monomethyl ether 550.

Other compositions containing other polyorthoesters, e.g. thosecontaining diketene acetals of formula IV and those containing otherdiols of formulae HO—R¹—OH, HO—R²—OH, HO—R³—OH, and HO—R⁴—OH, anddifferent active agents, and/or in different proportions are prepared ina similar manner.

Example 3 Release Profiles of the Pharmaceutical Compositions

The semi-solid compositions of Example 2 were weighed, placed intobottles with screw caps. 100 mL of 50 mM PBS (pH 7.4) was added to eachbottle. The test bottles were transferred to a 37° C. incubator andplaced on top of a rotor shaker (36 rpm). At various time points,bottles were removed from the incubator and samples of about 5 mL wereremoved and analyzed for bupivacaine content by HPLC at 263 nm. Theremaining volume of buffer was removed and replaced with 100 mL freshbuffer.

Composition B had an increased rate of release over the controlComposition A.

Composition D had a similar release rate as the control Composition C.

These test results demonstrated that the pharmaceutical compositions ofthe present invention have the advantage that the release rates of thecomposition may be adjusted and controlled in a variety of ways. Therates of release can be adjusted to accommodate a desired therapeuticeffect by either altering the mole percentage of the α-hydroxyacidcontaining units in the polyorthoester as disclosed in U.S. Pat. No.5,968,543, or by selecting a particular excipient, or by altering theconcentration of the excipient in the composition, or the combination ofall these factors.

The compositions can be irradiated, and the release rate of CompositionE before and after irradiation showed no significant difference overtwelve days using the test described above.

The foregoing is offered primarily for purposes of illustration. It willbe readily apparent to those skilled in the art that the molecularstructures, proportions of the various components in the deliveryvehicle or pharmaceutical composition, method of manufacture and otherparameters of the invention described herein may be further modified orsubstituted in various ways without departing from the spirit and scopeof the invention. For example, effective dosages other than theparticular dosages as set forth herein above may be applicable as aconsequence of variations in the responsiveness of the mammal beingtreated for any of the indications with the compounds of the inventionindicated above. Likewise, the specific pharmacological responsesobserved may vary according to and depending upon the particular activecompounds selected or whether there are present pharmaceutical carriers,as well as the type of formulation and mode of administration employed,and such expected variations or differences in the results arecontemplated in accordance with the objects and practices of the presentinvention. It is intended, therefore, that the invention be defined bythe scope of the claims which follow and that such claims be interpretedas broadly as is reasonable.

What is claimed is:
 1. A method for the prevention of nausea andvomiting in a patient in need thereof comprising administering to thepatient a pharmaceutical composition comprising: (A) a semi-soliddelivery vehicle, comprising: (i) a polyorthoester of formula I:

where: R* is ethyl; n is an integer of 5 to 1000; and A is R¹ or R³,where R¹ is:

where: p is an integer of 1 to 20; R⁵ is hydrogen; and R⁶ is:

where: s is an integer of 0 to 10; R³ is:

where: x is an integer of 0 to 30; in which about 0.05 to 30 mol percentof the A units are of the formula R¹; and (ii) polyethylene glycolmonomethyl ether; and (B) granisetron in an amount of 1 to 5 weight % ofthe composition.
 2. The method of claim 1, wherein the nausea andvomiting is associated with chemotherapy.
 3. The method of claim 1,wherein the nausea and vomiting is acute or delayed.
 4. The method ofclaim 1, wherein the composition is administered to the patient incombination with another antiemetic.
 5. The method of claim 3, whereinthe composition is administered to the patient in combination withanother antiemetic.
 6. The method of claim 1, wherein the administeringis by injection.
 7. The method of claim 1, wherein the administering isby subcutaneous injection.
 8. The method of claim 7, wherein theadministering is by a syringe with a 16 to 25 gauge needle.
 9. Themethod of claim 1, wherein the polyethylene glycol monomethyl ether hasa molecular weight between 200 and
 4000. 10. The method of claim 9,wherein the total concentration of the polyethylene glycol monomethylether is 5 to 60 weight % of the composition.
 11. The method of claim 1,wherein the polyethylene glycol monomethyl ether is polyethylene glycolmonomethyl ether
 550. 12. The method of claim 9, wherein thepolyethylene glycol monomethyl ether is polyethylene glycol monomethylether
 550. 13. The method of claim 1, wherein the composition comprises78.4 weight % polyorthoester, 19.6 weight % polyethylene glycolmonomethyl ether and 2 weight % granisetron.
 14. The method of claim 1,wherein p is an integer of 1 to 7 in a portion of the units of formulaI.
 15. The method of claim 1, wherein x is 2 in a portion of the unitsof formula I.
 16. The method of claim 1, wherein s is 2 in a portion ofthe units of formula I.
 17. The method of claim 1, wherein the totalconcentration of the polyethylene glycol monomethyl ether is 5% to 80%weight percent of the composition.
 18. The method of claim 1, whereinabout 0.1 to 25 mol percent of the A units are of the formula R¹.